Benzoimidazol-2-yl pyrimidines and pyrazines as modulators of the histamine H4 receptor

ABSTRACT

Benzoimidazol-2-yl pyrimidines and pyrazines, pharmaceutical compositions and methods for H 4  receptor activity modulation and for the treatment of disease states, disorders, and conditions mediated by H 4  receptor activity, including allergy, asthma, autoimmune diseases, and pruritis.

This application is a continuation of U.S. patent application Ser. No.12/816,995, filed Jun. 16, 2010, which in turn is a continuation of U.S.patent application Ser. No. 12/321,208, filed Jan. 15, 2009, nowabandoned, which in turn is a continuation of U.S. patent applicationSer. No. 11/731,074, filed Mar. 30, 2007, now U.S. Pat. No. 7,507,737,issued on Mar. 24, 2009, which claims the benefit of U.S. provisionalpatent application Ser. No. 60/788,190, filed on Mar. 31, 2006, all ofwhich are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to certain benzoimidazol-2-yl pyrimidinesand pyrazines, pharmaceutical compositions containing them, and methodsof using them for the treatment of disease states, disorders, andconditions mediated by histamine H₄ receptor activity.

BACKGROUND OF THE INVENTION

The histamine H₄ receptor (H₄R) is the most recently identified receptorfor histamine (for reviews, see: Fung-Leung, W.-P., et al., Curr. Opin.Invest. Drugs 2004, 5(11), 1174-1183; de Esch, I. J. P., et al., TrendsPharmacol. Sci. 2005, 26(9), 462-469). The receptor is found in the bonemarrow and spleen and is expressed on eosinophils, basophils, mast cells(Liu, C., et al., Mol. Pharmacol. 2001, 59(3), 420-426; Morse, K. L., etal., J. Pharmacol. Exp. Ther. 2001, 296(3), 1058-1066; Hofstra, C. L.,et al., J. Pharmacol. Exp. Ther. 2003, 305(3), 1212-1221; Lippert, U.,et al., J. Invest. Dermatol. 2004, 123(1), 116-123; Voehringer, D., etal., Immunity 2004, 20(3), 267-277), CD8⁺ T cells (Gantner, F., et al.,J. Pharmacol. Exp. Ther. 2002, 303(1), 300-307), dendritic cells, andhuman synovial cells from rheumatoid arthritis patients (Ikawa, Y., etal., Biol. Pharm. Bull. 2005, 28(10), 2016-2018). However, expression inneutrophils and monocytes is less well defined (Ling, P., et al., Br. J.Pharmacol. 2004, 142(1), 161-171). Receptor expression is at least inpart controlled by various inflammatory stimuli (Coge, F., et al.,Biochem. Biophys. Res. Commun. 2001, 284(2), 301-309; Morse, et al.,2001), thus supporting that H₄ receptor activation influencesinflammatory responses. Because of its preferential expression onimmunocompetent cells, the H₄ receptor is closely related with theregulatory functions of histamine during the immune response.

A biological activity of histamine in the context of immunology andautoimmune diseases is closely related with the allergic response andits deleterious effects, such as inflammation. Events that elicit theinflammatory response include physical stimulation (including trauma),chemical stimulation, infection, and invasion by a foreign body. Theinflammatory response is characterized by pain, increased temperature,redness, swelling, reduced function, or a combination of these.

Mast cell degranulation (exocytosis) releases histamine and leads to aninflammatory response that may be initially characterized by ahistamine-modulated wheal and flare reaction. A wide variety ofimmunological stimuli (e.g., allergens or antibodies) andnon-immunological (e.g., chemical) stimuli may cause the activation,recruitment, and de-granulation of mast cells. Mast cell activationinitiates allergic inflammatory responses, which in turn cause therecruitment of other effector cells that further contribute to theinflammatory response. It has been shown that histamine induceschemotaxis of mouse mast cells (Hofstra, et al., 2003). Chemotaxis doesnot occur using mast cells derived from H₄ receptor knockout mice.Furthermore, the response is blocked by an H₄-specific antagonist, butnot by H₁, H₂ or H₃ receptor antagonists (Hofstra, et al., 2003;Thurmond, R. L., et al., J. Pharmacol. Exp. Ther. 2004, 309(1),404-413). The in vivo migration of mast cells to histamine has also beeninvestigated and shown to be H₄ receptor dependent (Thurmond, et al.,2004). The migration of mast cells may play a role in allergic rhinitisand allergy where increases in mast cell number are found (Kirby, J. G.,et al., Am. Rev. Respir. Dis. 1987, 136(2), 379-383; Crimi, E., et al.,Am. Rev. Respir. Dis. 1991, 144(6), 1282-1286; Amin, K., et al., Am. J.Resp. Crit. Care Med. 2000, 162(6), 2295-2301; Gauvreau, G. M., et al.,Am. J. Resp. Crit. Care Med. 2000, 161(5), 1473-1478; Kassel, O., etal., Clin. Exp. Allergy 2001, 31(9), 1432-1440). In addition, it isknown that in response to allergens there is a redistribution of mastcells to the epithelial lining of the nasal mucosa (Fokkens, W. J., etal., Clin. Exp. Allergy 1992, 22(7), 701-710; Slater, A., et al., J.Laryngol. Otol. 1996, 110, 929-933). These results show that thechemotactic response of mast cells is mediated by histamine H₄receptors.

It has been shown that eosinophils can chemotax towards histamine(O'Reilly, M., et al., J. Recept. Signal Transduction 2002, 22(1-4),431-448; Buckland, K. F., et al., Br. J. Pharmacol. 2003, 140(6),1117-1127; Ling et al., 2004). Using H₄ selective ligands, it has beenshown that histamine-induced chemotaxis of eosinophils is mediatedthrough the H₄ receptor (Buckland, et al., 2003; Ling et al., 2004).Cell surface expression of adhesion molecules CD11b/CD18 (LFA-1) andCD54 (ICAM-1) on eosinophils increases after histamine treatment (Ling,et al., 2004). This increase is blocked by H₄ receptor antagonists butnot by H₁, H₂, or H₃ receptor antagonists.

The H₄R also plays a role in dendritic cells and T cells. In humanmonocyte-derived dendritic cells, H₄R stimulation suppresses IL-12p70production and drives histamine-mediated chemotaxis (Gutzmer, R., etal., J. Immunol. 2005, 174(9), 5224-5232). A role for the H₄ receptor inCD8⁺ T cells has also been reported. Gantner, et al., (2002) showed thatboth H₄ and H₂ receptors control histamine-induced IL-16 release fromhuman CD8⁺ T cells. IL-16 is found in the bronchoalveolar fluid ofallergen- or histamine-challenged asthmatics (Mashikian, V. M., et al.,J. Allergy Clin. Immunol. 1998, 101 (6, Part 1), 786-792; Krug, N., etal., Am. J. Resp. Grit. Care Med. 2000, 162(1), 105-111) and isconsidered important in CD4⁺ cell migration. The activity of thereceptor in these cell types indicates an important role in adaptiveimmune responses such as those active in autoimmune diseases.

In vivo H₄ receptor antagonists were able to block neutrophillia inzymosan-induced peritonitis or pleurisy models (Takeshita, K., et al.,J. Pharmacol. Exp. Ther. 2003, 307(3), 1072-1078; Thurmond, et al.,2004). In addition, H₄ receptor antagonists have activity in a widelyused and well-characterized model of colitis (Varga, C., et al., Eur. J.Pharmacol. 2005, 522(1-3), 130-138). These results support theconclusion that H₄ receptor antagonists have the capacity to beanti-inflammatory in vivo.

Another physiological role of histamine is as a mediator of itch and H₁receptor antagonists are not completely effective in the clinic.Recently, the H₄ receptor has also been implicated in histamine-inducedscratching in mice (Bell, J. K., et al., Br. J. Pharmacol. 2004, 142(2),374-380). The effects of histamine could be blocked by H₄ antagonists.These results support the hypothesis that the H₄ receptor is involved inhistamine-induced itch and that H₄ receptor antagonists will thereforehave positive effects in treating pruritis.

Modulation of H₄ receptors controls the release of inflammatorymediators and inhibits leukocyte recruitment, thus providing the abilityto prevent and/or treat H₄-mediated diseases and conditions, includingthe deleterious effects of allergic responses such as inflammation.Compounds according to the present invention have H₄ receptor modulatingproperties. Compounds according to the present invention have leukocyterecruitment inhibiting properties. Compounds according to the presentinvention have anti-inflammatory properties.

Examples of textbooks on the subject of inflammation include: 1) Gallin,J. I.; Snyderman, R., Inflammation: Basic Principles and ClinicalCorrelates, 3rd ed.; Lippincott Williams & Wilkins: Philadelphia, 1999;2) Stvrtinova, V., et al., Inflammation and Fever. PathophysiologyPrinciples of Diseases (Textbook for Medical Students); Academic Press:New York, 1995; 3) Cecil; et al. Textbook Of Medicine, 18th ed.; W.B.Saunders Co., 1988; and 4) Stedman's Medical Dictionary.

Background and review material on inflammation and conditions relatedwith inflammation can be found in articles such as the following:Nathan, C., Nature 2002, 420(6917), 846-852; Tracey, K. J., Nature 2002,420(6917), 853-859; Coussens, L. M., et al., Nature 2002, 420(6917),860-867; Libby, P., Nature 2002, 420, 868-874; Benoist, C., et al.,Nature 2002, 420(6917), 875-878; Weiner, H. L., et al., Nature 2002,420(6917), 879-884; Cohen, J., Nature 2002, 420(6917), 885-891;Steinberg, D., Nature Med. 2002, 8(11), 1211-1217.

Thus, small-molecule histamine H₄ receptor modulators according to thisinvention control the release of inflammatory mediators and inhibitleukocyte recruitment, and may be useful in treating inflammation ofvarious etiologies, including the following conditions and diseases:inflammatory disorders, allergic disorders, dermatological disorders,autoimmune disease, lymphatic disorders, pruritis, and immunodeficiencydisorders. Diseases, disorders and medical conditions that are mediatedby histamine H₄ receptor activity include those referred to herein.

2-Arylbenzimidazoles have been described as histamine H₄ receptormodulators, see, for example, U.S. Pat. Appl. Publ. 2005/0070550A1.However, there still remains a need for potent histamine H₄ receptormodulators with desirable pharmaceutical properties.

SUMMARY OF THE INVENTION

Certain benzoimidazol-2-yl pyrimidines and pyrazines have now been foundto have histamine H₄ receptor-modulating activity.

In one general aspect, the invention relates to compounds of thefollowing Formula (I):

wherein

-   each of R¹⁻⁴ is independently H, C₁₋₄alkyl, C₂₋₄alkenyl,    C₂₋₄alkynyl, phenyl, —OF₃, —OCF₃, —CN, halo, —NO₂, —OC₁₋₄alkyl,    —SC₁₋₄alkyl, —S(O)C₁₋₄alkyl, —SO₂C₁₋₄alkyl, —C(O)C₁₋₄alkyl,    —C(O)phenyl, —C(O)NR^(a)R^(b), —CO₂C₁₋₄alkyl, —CO₂H,    —C(O)NR^(a)R^(b), or —NR^(a)R^(b); wherein R^(a) and R^(b) are each    independently H, C₁₋₄alkyl, or C₃₋₇cycloalkyl;-   one of X¹ and X² is N and the other is C—R^(c);    -   where R^(c) is H, methyl, hydroxymethyl, dimethylaminomethyl,        ethyl, propyl, isopropyl, —CF₃, cyclopropyl, or cyclobutyl;-   n is 1 or 2;-   Z is N, CH, or C(C₁₋₄alkyl);-   R⁶ is H, C₁₋₆alkyl, or monocyclic cycloalkyl;-   R⁸ is H or C₁₋₄alkyl;-   R⁹ and R¹⁰ are each independently H or C₁₋₄alkyl; and-   R¹¹ is H or C₁₋₄alkyl.

This invention also relates to any of the following: pharmaceuticallyacceptable salts of compounds of Formula (I), pharmaceuticallyacceptable prodrugs of compounds of Formula (I), and pharmaceuticallyactive metabolites of compounds of Formula (I).

In other embodiments, the compound of Formula (I) is a compound selectedfrom those species described or exemplified in the detailed descriptionbelow.

In a further general aspect, the invention relates to pharmaceuticalcompositions each comprising: (a) an effective amount of at least oneagent selected from compounds of Formula (I) and pharmaceuticallyacceptable salts, pharmaceutically acceptable prodrugs, andpharmaceutically active metabolites thereof; and (b) a pharmaceuticallyacceptable excipient.

In another general aspect, the invention is directed to a method oftreating a subject suffering from or diagnosed with a disease, disorder,or medical condition mediated by histamine H₄ receptor activity,comprising administering to the subject in need of such treatment aneffective amount of at least one compound of Formula (I), or apharmaceutically acceptable salt, pharmaceutically acceptable prodrug,or pharmaceutically active metabolite of such compound. In certainpreferred embodiments of the inventive method, the disease, disorder, ormedical condition is inflammation. Inflammation herein refers to theresponse that develops as a consequence of histamine release, which inturn is caused by at least one stimulus. Examples of such stimuli areimmunological stimuli and non-immunological stimuli.

In another general aspect, the invention is directed to a method formodulating histamine H₄ receptor activity, comprising exposing histamineH₄ receptor to an effective amount of at least one of a compound ofFormula (I) and a salt thereof.

Additional embodiments, features, and advantages of the invention willbe apparent from the following detailed description and through practiceof the invention.

DETAILED DESCRIPTION OF INVENTION

The invention may be more fully appreciated by reference to thefollowing description, including the following glossary of terms and theconcluding examples. For the sake of brevity, the disclosures of thepublications, including patents, cited in this specification are hereinincorporated by reference.

As used herein, the terms “including”, “containing” and “comprising” areused herein in their open, non-limiting sense.

The term “alkyl” refers to a straight- or branched-chain alkyl grouphaving from 1 to 12 carbon atoms in the chain. Examples of alkyl groupsinclude methyl (Me, which also may be structurally depicted by thesymbol “/”), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl,isohexyl, and groups that in light of the ordinary skill in the art andthe teachings provided herein would be considered equivalent to any oneof the foregoing examples.

The term “alkenyl” refers to a straight- or branched-chain alkenyl grouphaving from 2 to 12 carbon atoms in the chain. (The double bond of thealkenyl group is formed by two sp² hybridized carbon atoms.)Illustrative alkenyl groups include prop-2-enyl, but-2-enyl, but-3-enyl,2-methylprop-2-enyl, hex-2-enyl, and groups that in light of theordinary skill in the art and the teachings provided herein would beconsidered equivalent to any one of the foregoing examples.

The term “cycloalkyl” refers to a saturated or partially saturated,monocyclic, fused polycyclic, or spiro polycyclic carbocycle having from3 to 12 ring atoms per carbocycle. Illustrative examples of cycloalkylgroups include the following entities, in the form of properly bondedmoieties:

A “heterocycloalkyl” refers to a monocyclic, or fused, bridged, or spiropolycyclic ring structure that is saturated or partially saturated andhas from 3 to 12 ring atoms per ring structure selected from carbonatoms and up to three heteroatoms selected from nitrogen, oxygen, andsulfur. The ring structure may optionally contain up to two oxo groupson carbon or sulfur ring members. Illustrative entities, in the form ofproperly bonded moieties, include:

The term “heteroaryl” refers to a monocyclic, fused bicyclic, or fusedpolycyclic aromatic heterocycle (ring structure having ring atomsselected from carbon atoms and up to four heteroatoms selected fromnitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms perheterocycle. Illustrative examples of heteroaryl groups include thefollowing entities, in the form of properly bonded moieties:

Those skilled in the art will recognize that the species of heteroaryl,cycloalkyl, and heterocycloalkyl groups listed or illustrated above arenot exhaustive, and that additional species within the scope of thesedefined terms may also be selected.

The term “halogen” represents chlorine, fluorine, bromine, or iodine.The term “halo” represents chloro, fluoro, bromo, or iodo.

The term “substituted” means that the specified group or moiety bearsone or more substituents. The term “unsubstituted” means that thespecified group bears no substituents. The term “optionally substituted”means that the specified group is unsubstituted or substituted by one ormore substituents. Where the term “substituted” is used to describe astructural system, the substitution is meant to occur at anyvalency-allowed position on the system.

Any formula given herein is intended to represent compounds havingstructures depicted by the structural formula as well as certainvariations or forms. In particular, compounds of any formula givenherein may have asymmetric centers and therefore exist in differentenantiomeric forms. All optical isomers and stereoisomers of thecompounds of the general formula, and mixtures thereof, are consideredwithin the scope of the formula. Thus, any formula given herein isintended to represent a racemate, one or more enantiomeric forms, one ormore diastereomeric forms, one or more atropisomeric forms, and mixturesthereof.

Furthermore, certain structures may exist as geometric isomers (i.e.,cis and trans isomers), as tautomers, or as atropisomers. Additionally,any formula given herein is intended to represent hydrates, solvates,and polymorphs of such compounds, and mixtures thereof.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that, whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including equivalents and approximations due to the experimentaland/or measurement conditions for such given value. Whenever a yield isgiven as a percentage, such yield refers to a mass of the entity forwhich the yield is given with respect to the maximum amount of the sameentity that could be obtained under the particular stoichiometricconditions. Concentrations that are given as percentages refer to massratios, unless indicated differently.

Reference to a chemical entity herein stands for a reference to any oneof: (a) the actually recited form of such chemical entity, and (b) anyof the forms of such chemical entity in the medium in which the compoundis being considered when named. For example, reference herein to acompound such as R—COOH, encompasses reference to any one of, forexample, R—COOH_((s)), R—COOH_((sol)), and R—COO⁻ _((sol)). In thisexample, R—COOH_((s)) refers to the solid compound, as it could be forexample in a tablet or some other solid pharmaceutical composition orpreparation; R—COOH_((sol)) refers to the undissociated form of thecompound in a solvent; and R—COO⁻ _((sol)) refers to the dissociatedform of the compound in a solvent, such as the dissociated form of thecompound in an aqueous environment, whether such dissociated formderives from R—COOH, from a salt thereof, or from any other entity thatyields R—COO⁻ upon dissociation in the medium being considered. Inanother example, an expression such as “exposing an entity to compoundof formula R—COOH” refers to the exposure of such entity to the form, orforms, of the compound R—COOH that exists, or exist, in the medium inwhich such exposure takes place. In this regard, if such entity is forexample in an aqueous environment, it is understood that the compoundR—COOH is in such same medium, and therefore the entity is being exposedto species such as R—COOH_((aq)) and/or R—COO⁻ _((aq)), where thesubscript “(aq)” stands for “aqueous” according to its conventionalmeaning in chemistry and biochemistry. A carboxylic acid functionalgroup has been chosen in these nomenclature examples; this choice is notintended, however, as a limitation but it is merely an illustration. Itis understood that analogous examples can be provided in terms of otherfunctional groups, including but not limited to hydroxyl, basic nitrogenmembers, such as those in amines, and any other group that interacts ortransforms according to known manners in the medium that contains thecompound. Such interactions and transformations include, but are notlimited to, dissociation, association, tautomerism, solvolysis,including hydrolysis, solvation, including hydration, protonation, anddeprotonation. In another example, a zwitterionic compound isencompassed herein by referring to a compound that is known to form azwitterions, even if it is not explicitly named in its zwitterionicform. Terms such as zwitterion, zwitterions, and their synonymszwitterionic compound(s) are standard IUPAC-endorsed names that are wellknown and part of standard sets of defined scientific names. In thisregard, the name zwitterion is assigned the name identificationCHEBI:27369 by the Chemical Entities of Biological Inerest (ChEBI)dictionary of molecular entities. (See, for example its on line versionat http://www.ebi.ac.uk/chebi/init.do). As generally well known, azwitterion or zwitterionic compound is a neutral compound that hasformal unit charges of opposite sign. Sometimes these compounds arereferred to by the term “inner salts”. Other sources refer to thesecompounds as “dipolar ions”, although the latter term is regarded bystill other sources as a misnomer. As a specific example, aminoethanoicacid (the amino acid glycine) has the formula H₂NCH₂COOH, and it existsin some media (in this case in neutral media) in the form of thezwitterion ⁺H₃NCH₂COO⁻. Zwitterions, zwitterionic compounds, inner saltsand dipolar ions in the known and well established meanings of theseterms are within the scope of this invention, as would in any case be soappreciated by those of ordinary skill in the art. Because there is noneed to name each and every embodiment that would be recognized by thoseof ordinary skill in the art, no structures of the zwitterioniccompounds that are associated with the compounds of this invention aregiven explicitly herein. They are, however, part of the embodiments ofthis invention. No further examples in this regard are provided hereinbecause these interactions and transformations in a given medium areknown by any one of ordinary skill in the art.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, andiodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S,¹⁸F, ³⁶Cl, ¹²⁵I, respectively. Such isotopically labelled compounds areuseful in metabolic studies (preferably with ¹⁴C), reaction kineticstudies (with, for example ²H or ³H), detection or imaging techniques[such as positron emission tomography (PET) or single-photon emissioncomputed tomography (SPECT)] including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Inparticular, an ¹⁸F or ¹¹C labeled compound may be particularly preferredfor PET or SPECT studies. Further, substitution with heavier isotopessuch as deuterium (i.e., ²H) may afford certain therapeutic advantagesresulting from greater metabolic stability, for example increased invivo half-life or reduced dosage requirements. Isotopically labeledcompounds of this invention and prodrugs thereof can generally beprepared by carrying out the procedures disclosed in the schemes or inthe examples and preparations described below by substituting a readilyavailable isotopically labeled reagent for a non-isotopically labeledreagent.

When referring to any formula given herein, the selection of aparticular moiety from a list of possible species for a specifiedvariable is not intended to define the same choice of the species forthe variable appearing elsewhere. In other words, where a variableappears more than once, the choice of the species from a specified listis independent of the choice of the species for the same variableelsewhere in the formula, unless stated otherwise.

By way of a first example on substituent terminology, if substituent S¹_(example) is one of S₁ and S₂, and substituent S² _(example) is one ofS₃ and S₄, then these assignments refer to embodiments of this inventiongiven according to the choices S¹ _(example) is S₁ and S² _(example) isS₃; S¹ _(example) is S₁ and S² _(example) is S₄; S¹ _(example) is S₂ andS² _(example) is S₃; S¹ _(example) is S₂ and S² _(example) is S₄; andequivalents of each one of such choices. The shorter terminology “S¹_(example) is one of S₁ and S₂, and S² _(example) is one of S₃ and S₄”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing first example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein. The foregoing convention givenherein for substituents extends, when applicable, to members such asR¹⁻¹¹, X¹, X², and n, and any other generic substituent symbol usedherein.

Furthermore, when more than one assignment is given for any member orsubstituent, embodiments of this invention comprise the variousgroupings that can be made from the listed assignments, takenindependently, and equivalents thereof. By way of a second example onsubstituent terminology, if it is herein described that substituentS_(example) is one of S₁, S₂, and S₃, this listing refers to embodimentsof this invention for which S_(example) is S₁; S_(example) is S₂;S_(example) is S₃; S_(example) is one of S₁ and S₂; S_(example) is oneof S₁ and S₃; S_(example) is one of S₂ and S₃; S_(example) is one of S₁,S₂ and S₃; and S_(example) is any equivalent of each one of thesechoices. The shorter terminology “S_(example) is one of S₁, S₂, and S₃”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing second example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein. The foregoing convention givenherein for substituents extends, when applicable, to members such asR¹⁻¹¹, X¹, X², and n, and any other generic substituent symbol usedherein.

The nomenclature “C_(i-j)” with j>i, when applied herein to a class ofsubstituents, is meant to refer to embodiments of this invention forwhich each and every one of the number of carbon members, from i to jincluding i and j, is independently realized. By way of example, theterm C₁₋₃ refers independently to embodiments that have one carbonmember (C₁), embodiments that have two carbon members (C₂), andembodiments that have three carbon members (C₃).

The term C_(n-m)alkyl refers to an aliphatic chain, whether straight orbranched, with a total number N of carbon members in the chain thatsatisfies n≦N≦m, with m>n.

Any disubstituent referred to herein is meant to encompass the variousattachment possibilities when more than one of such possibilities areallowed. For example, reference to disubstituent -A-B-, where A≠B,refers herein to such disubstituent with A attached to a firstsubstituted member and B attached to a second substituted member, and italso refers to such disubstituent with A attached to the secondsubstituted member and B attached to the first substituted member.

According to the foregoing interpretive considerations on assignmentsand nomenclature, it is understood that explicit reference herein to aset implies, where chemically meaningful and unless indicated otherwise,independent reference to embodiments of such set, and reference to eachand every one of the possible embodiments of subsets of the set referredto explicitly.

In some embodiments of Formula (I), each of R¹⁻⁴ is independently H,methyl, tert-butyl, methoxy, —CF₃, —CN, fluoro, chloro, methoxycarbonyl,or benzoyl.

In some embodiments, X² is N. In other embodiments, X¹ is N.

In some embodiments, R^(c) is H, methyl, ethyl, CF₃, cyclopropyl, orcyclobutyl. In further embodiments, R^(c) is H or methyl.

In some embodiments, n is 1.

In some embodiments, Z is N or CH. In further embodiments, Z is CH.

In some embodiments, R⁶ is H, methyl, ethyl, propyl, isopropyl,cyclopropyl, or cyclobutyl. In further embodiments, R⁶ is H or methyl.

In some embodiments, R⁸ is H.

In some embodiments, R⁹ and R¹⁰ are each independently H or methyl. Infurther embodiments, R⁹ and R¹⁰ are both H.

In some embodiments, R¹¹ is H or methyl. In further embodiments, R¹¹ ismethyl.

The invention includes also pharmaceutically acceptable salts of thecompounds represented by Formula (I), preferably of those describedabove and of the specific compounds exemplified herein.

A “pharmaceutically acceptable salt” is intended to mean a salt of afree acid or base of a compound represented by Formula (I) that isnon-toxic, biologically tolerable, or otherwise biologically suitablefor administration to the subject. See, generally, S. M. Berge, et al.,“Pharmaceutical Salts”, J. Pharm. Sci., 1977, 66:1-19, and Handbook ofPharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth,Eds., Wiley-VCH and VHCA, Zurich, 2002. Examples of pharmaceuticallyacceptable salts are those that are pharmacologically effective andsuitable for contact with the tissues of patients without unduetoxicity, irritation, or allergic response. A compound of Formula (I)may possess a sufficiently acidic group, a sufficiently basic group, orboth types of functional groups, and accordingly react with a number ofinorganic or organic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt. Examples of pharmaceuticallyacceptable salts include sulfates, pyrosulfates, bisulfates, sulfites,bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates,metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates,propionates, decanoates, caprylates, acrylates, formates, isobutyrates,caproates, heptanoates, propiolates, oxalates, malonates, succinates,suberates, sebacates, fumarates, maleates, butyne-1,4-dioates,hexyne-1,6-dioates, benzoates, chlorobenzoates, methyl benzoates,dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates,sulfonates, xylenesulfonates, phenylacetates, phenylpropionates,phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates,tartrates, methane-sulfonates, propanesulfonates,naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

If the compound of Formula (I) contains a basic nitrogen, the desiredpharmaceutically acceptable salt may be prepared by any suitable methodavailable in the art, for example, treatment of the free base with aninorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuricacid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and thelike, or with an organic acid, such as acetic acid, phenylacetic acid,propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid,hydroxymaleic acid, isethionic acid, succinic acid, valeric acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidylacid, such as glucuronic acid or galacturonic acid, an alpha-hydroxyacid, such as mandelic acid, citric acid, or tartaric acid, an aminoacid, such as aspartic acid or glutamic acid, an aromatic acid, such asbenzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, asulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid,methanesulfonic acid, ethanesulfonic acid, any compatible mixture ofacids such as those given as examples herein, and any other acid andmixture thereof that are regarded as equivalents or acceptablesubstitutes in light of the ordinary level of skill in this technology.

If the compound of Formula (I) is an acid, such as a carboxylic acid orsulfonic acid, the desired pharmaceutically acceptable salt may beprepared by any suitable method, for example, treatment of the free acidwith an inorganic or organic base, such as an amine (primary, secondaryor tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide,any compatible mixture of bases such as those given as examples herein,and any other base and mixture thereof that are regarded as equivalentsor acceptable substitutes in light of the ordinary level of skill inthis technology. Illustrative examples of suitable salts include organicsalts derived from amino acids, such as glycine and arginine, ammonia,carbonates, bicarbonates, primary, secondary, and tertiary amines, andcyclic amines, such as benzylamines, pyrrolidines, piperidine,morpholine, and piperazine, and inorganic salts derived from sodium,calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum,and lithium.

The invention also relates to treatment methods employingpharmaceutically acceptable prodrugs of the compounds of Formula (I).The term “prodrug” means a precursor of a designated compound that,following administration to a subject, yields the compound in vivo via achemical or physiological process such as solvolysis or enzymaticcleavage, or under physiological conditions (e.g., a prodrug on beingbrought to physiological pH is converted to the compound of Formula(I)). A “pharmaceutically acceptable prodrug” is a prodrug that is nottoxic, biologically intolerable, or otherwise biologically unsuitablefor administration to the subject. Illustrative procedures for theselection and preparation of suitable prodrug derivatives are described,for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Examples of prodrugs include compounds having an amino acid residue, ora polypeptide chain of two or more (e.g., two, three or four) amino acidresidues, covalently joined through an amide or ester bond to a freeamino, hydroxy, or carboxylic acid group of a compound of Formula (I).Examples of amino acid residues include the twenty naturally occurringamino acids, commonly designated by three letter symbols, as well as4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline homocysteine, homoserine, ornithine and methionine sulfone.

Additional types of prodrugs may be produced, for instance, byderivatizing free carboxyl groups of structures of Formula (I) as amidesor alkyl esters. Examples of amides include those derived from ammonia,primary C₁₋₆alkyl amines and secondary di(C₁₋₆alkyl) amines. Secondaryamines include 5- or 6-membered heterocycloalkyl or heteroaryl ringmoieties. Examples of amides include those that are derived fromammonia, C₁₋₃alkyl primary amines, and di(C₁₋₂alkyl)amines. Examples ofesters of the invention include C₁₋₇alkyl, C₅₋₇cycloalkyl, phenyl, andphenyl(C₁₋₆alkyl) esters. Preferred esters include methyl esters.Prodrugs may also be prepared by derivatizing free hydroxy groups usinggroups including hemisuccinates, phosphate esters,dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, followingprocedures such as those outlined in Adv. Drug Delivery Rev. 1996, 19,115. Carbamate derivatives of hydroxy and amino groups may also yieldprodrugs. Carbonate derivatives, sulfonate esters, and sulfate esters ofhydroxy groups may also provide prodrugs. Derivatization of hydroxygroups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acylgroup may be an alkyl ester, optionally substituted with one or moreether, amine, or carboxylic acid functionalities, or where the acylgroup is an amino acid ester as described above, is also useful to yieldprodrugs. Prodrugs of this type may be prepared as described in J. Med.Chem. 1996, 39, 10. Free amines can also be derivatized as amides,sulfonamides or phosphonamides. All of these prodrug moieties mayincorporate groups including ether, amine, and carboxylic acidfunctionalities.

Pharmaceutically active metabolites may also be used in the methods ofthe invention. A “pharmaceutically active metabolite” means apharmacologically active product of metabolism in the body of a compoundof Formula (I) or salt thereof. Prodrugs and active metabolites of acompound may be determined using routine techniques known or availablein the art. See, e.g., Bertolini, et al., J. Med. Chem. 1997, 40,2011-2016; Shan, et al., J. Pharm. Sci. 1997, 86 (7), 765-767; Bagshawe,Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984, 13,224-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); andLarsen, Design and Application of Prodrugs, Drug Design and Development(Krogsgaard-Larsen, et al., eds., Harwood Academic Publishers, 1991).

The compounds of Formula (I) and their pharmaceutically acceptablesalts, pharmaceutically acceptable prodrugs, and pharmaceutically activemetabolites (collectively, “agents”) of the present invention are usefulas histamine H₄ receptor modulators in the methods of the invention. Theagents may be used in the inventive methods for the treatment orprevention of medical conditions, diseases, or disorders mediatedthrough modulation of the histamine H₄ receptor, such as those describedherein. Agents according to the invention may therefore be used as ananti-inflammatory agents. Symptoms or disease states are intended to beincluded within the scope of “medical conditions, disorders, ordiseases.”

Accordingly, the invention relates to methods of using thepharmaceutical agents described herein to treat subjects diagnosed withor suffering from a disease, disorder, or condition mediated throughhistamine H₄ receptor activity, such as inflammation.

In a preferred embodiment, an agent of the present invention isadministered to treat inflammation. Inflammation may be associated withvarious diseases, disorders, or conditions, such as inflammatorydisorders, allergic disorders, dermatological disorders, autoimmunedisease, lymphatic disorders, and immunodeficiency disorders, includingthe more specific conditions and diseases given below. Regarding theonset and evolution of inflammation, inflammatory diseases orinflammation-mediated diseases or conditions include, but are notlimited to, acute inflammation, allergic inflammation, and chronicinflammation.

Illustrative types of inflammation treatable with a histamine H₄receptor-modulating agent according to the invention includeinflammation due to or associated with any one of a plurality ofconditions such as allergy, asthma, dry eye, chronic obstructedpulmonary disease (COPD), atherosclerosis, rheumatoid arthritis,multiple sclerosis, inflammatory bowel diseases (including colitis,Crohn's disease, and ulcerative colitis), psoriasis, pruritis, itchyskin, atopic dermatitis, urticaria (hives), ocular inflammation,conjunctivitis, nasal polyps, allergic rhinitis, nasal itch,scleroderma, autoimmune thyroid diseases, immune-mediated (also known astype 1) diabetes mellitus and lupus, which are characterized byexcessive or prolonged inflammation at some stage of the disease. Otherautoimmune diseases that lead to inflammation include Myasthenia gravis,autoimmune neuropathies, such as Guillain-Barré, autoimmune uveitis,autoimmune hemolytic anemia, pernicious anemia, autoimmunethrombocytopenia, temporal arteritis, anti-phospholipid syndrome,vasculitides, such as Wegener's granulomatosis, Behcet's disease,dermatitis herpetiformis, pemphigus vulgaris, vitiligio, primary biliarycirrhosis, autoimmune hepatitis, autoimmune oophoritis and orchitis,autoimmune disease of the adrenal gland, polymyositis, dermatomyositis,spondyloarthropathies, such as ankylosing spondylitis, and Sjogren'ssyndrome.

Pruritis with a histamine H₄ receptor-modulating agent according to theinvention includes that which is a symptom of allergic cutaneousdiseases (such as atopic dermatitis and hives) and other metabolicdisorders (such as chronic renal failure, hepatic cholestasis, anddiabetes mellitus).

In another preferred embodiment, an agent of the present invention isadministered to treat allergy, asthma, autoimmune diseases, or pruritis.

The term “treat” or “treating” as used herein is intended to refer toadministration of an agent or composition of the invention to a subjectfor the purpose of effecting a therapeutic or prophylactic benefitthrough modulation of histamine H₄ receptor activity. Treating includesreversing, ameliorating, alleviating, inhibiting the progress of,lessening the severity of, or preventing a disease, disorder, orcondition, or one or more symptoms of such disease, disorder orcondition mediated through modulation of histamine H₄ receptor activity.The term “subject” refers to a mammalian patient in need of suchtreatment, such as a human. “Modulators” include both inhibitors andactivators, where “inhibitors” refer to compounds that decrease,prevent, inactivate, desensitize or down-regulate histamine H₄ receptorexpression or activity, and “activators” are compounds that increase,activate, facilitate, sensitize, or up-regulate histamine H₄ receptorexpression or activity.

In treatment methods according to the invention, an effective amount ofat least one pharmaceutical agent according to the invention isadministered to a subject suffering from or diagnosed as having such adisease, disorder, or condition. An “effective amount” means an amountor dose sufficient to generally bring about the desired therapeutic orprophylactic benefit in patients in need of such treatment for thedesignated disease, disorder, or condition. Effective amounts or dosesof the agents of the present invention may be ascertained by routinemethods such as modeling, dose escalation studies or clinical trials,and by taking into consideration routine factors, e.g., the mode orroute of administration or drug delivery, the pharmacokinetics of theagent, the severity and course of the disease, disorder, or condition,the subject's previous or ongoing therapy, the subject's health statusand response to drugs, and the judgment of the treating physician. Anexample of a dose is in the range of from about 0.001 to about 200 mg ofagent per kg of subject's body weight per day, preferably about 0.05 to100 mg/kg/day, or about 1 to 35 mg/kg/day, in single or divided dosageunits (e.g., BID, TID, QID). For a 70-kg human, an illustrative rangefor a suitable dosage amount is from about 0.05 to about 7 g/day, orabout 0.2 to about 2.5 g/day.

Once improvement of the patient's disease, disorder, or condition hasoccurred, the dose may be adjusted for preventative or maintenancetreatment. For example, the dosage or the frequency of administration,or both, may be reduced as a function of the symptoms, to a level atwhich the desired therapeutic or prophylactic effect is maintained. Ofcourse, if symptoms have been alleviated to an appropriate level,treatment may cease. Patients may, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

In addition, the agents of the invention may be used in combination withadditional active compounds in the treatment of the above conditions.The additional compounds may be coadministered separately with an agentof Formula (I) or included with such an agent as an additional activeingredient in a pharmaceutical composition according to the invention.In an illustrative embodiment, additional active compounds are thosethat are known or discovered to be effective in the treatment ofconditions, disorders, or diseases mediated by histamine H₄ receptoractivity, such as another histamine H₄ receptor modulator or a compoundactive against another target associated with the particular condition,disorder, or disease. The combination may serve to increase efficacy(e.g., by including in the combination a compound potentiating thepotency or effectiveness of an agent according to the invention),decrease one or more side effects, or decrease the required dose of theagent according to the invention.

When referring to modulating the target receptor, an “effective amount”means an amount sufficient to affect the activity of such receptor.Measuring the activity of the target receptor may be performed byroutine analytical methods. Target receptor modulation is useful in avariety of settings, including assays.

The agents of the invention are used, alone or in combination with oneor more other active ingredients, to formulate pharmaceuticalcompositions of the invention. A pharmaceutical composition of theinvention comprises an effective amount of at least one pharmaceuticalagent in accordance with the invention. A pharmaceutically acceptableexcipient is part of some embodiments of pharmaceutical compositionsaccording to this invention.

A “pharmaceutically acceptable excipient” refers to a substance that isnot toxic, biologically intolerable, or otherwise biologicallyunsuitable for administration to a subject, such as an inert substance,added to a pharmacological composition or otherwise used as a vehicle,carrier, or diluent to facilitate administration of a pharmaceuticalagent and that is compatible therewith. Examples of excipients includecalcium carbonate, calcium phosphate, various sugars and types ofstarch, cellulose derivatives, gelatin, vegetable oils, and polyethyleneglycols.

Delivery forms of the pharmaceutical compositions containing one or moredosage units of the pharmaceutical agents may be prepared using suitablepharmaceutical excipients and compounding techniques known or thatbecome available to those skilled in the art. The compositions may beadministered in the inventive methods by a suitable route of delivery,e.g., oral, parenteral, rectal, topical, or ocular routes, or byinhalation.

The preparation may be in the form of tablets, capsules, sachets,dragees, powders, granules, lozenges, powders for reconstitution, liquidpreparations, or suppositories. Preferably, the compositions areformulated for intravenous infusion, topical administration, or oraladministration.

For oral administration, the compounds of the invention can be providedin the form of tablets or capsules, or as a solution, emulsion, orsuspension. To prepare the oral compositions, the agents may beformulated to yield a dosage of, e.g., from about 0.05 to about 50 mg/kgdaily, or from about 0.05 to about 20 mg/kg daily, or from about 0.1 toabout 10 mg/kg daily.

Oral tablets may include the agent and any other active ingredientsmixed with compatible pharmaceutically acceptable excipients such asdiluents, disintegrating agents, binding agents, lubricating agents,sweetening agents, flavoring agents, coloring agents and preservativeagents. Suitable inert fillers include sodium and calcium carbonate,sodium and calcium phosphate, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, and the like.Examples of liquid oral excipients include ethanol, glycerol, water, andthe like. Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate,microcrystalline cellulose, and alginic acid are examples ofdisintegrating agents. Binding agents may include starch and gelatin.The lubricating agent, if present, may be magnesium stearate, stearicacid or talc. If desired, the tablets may be coated with a material suchas glyceryl monostearate or glyceryl distearate to delay absorption inthe gastrointestinal tract, or may be coated with an enteric coating.

Capsules for oral administration include hard and soft gelatin capsules.To prepare hard gelatin capsules, active ingredient may be mixed with asolid, semi-solid, or liquid diluent. Soft gelatin capsules may beprepared by mixing the active ingredient with water, an oil such aspeanut oil or olive oil, liquid paraffin, a mixture of mono anddi-glycerides of short chain fatty acids, polyethylene glycol 400, orpropylene glycol.

Liquids for oral administration may be in the form of suspensions,solutions, emulsions or syrups or may be lyophilized or presented as adry product for reconstitution with water or other suitable vehiclebefore use. Such liquid compositions may optionally contain:pharmaceutically-acceptable excipients such as suspending agents (forexample, sorbitol, methyl cellulose, sodium alginate, gelatin,hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel andthe like); non-aqueous vehicles, e.g., oil (for example, almond oil orfractionated coconut oil), propylene glycol, ethyl alcohol, or water;preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbicacid); wetting agents such as lecithin; and, if desired, flavoring orcoloring agents.

The active agents of this invention may also be administered by non-oralroutes. For example, the compositions may be formulated for rectaladministration as a suppository. For parenteral use, includingintravenous, intramuscular, intraperitoneal, or subcutaneous routes, theagents of the invention may be provided in sterile aqueous solutions orsuspensions, buffered to an appropriate pH and isotonicity or inparenterally acceptable oil. Suitable aqueous vehicles include Ringer'ssolution and isotonic sodium chloride. Such forms may be presented inunit-dose form such as ampules or disposable injection devices, inmulti-dose forms such as vials from which the appropriate dose may bewithdrawn, or in a solid form or pre-concentrate that can be used toprepare an injectable formulation. Illustrative infusion doses rangefrom about 1 to 1000 μg/kg/minute of agent, admixed with apharmaceutical carrier over a period ranging from several minutes toseveral days.

For topical administration, the agents may be mixed with apharmaceutical carrier at a concentration of about 0.1% to about 10% ofdrug to vehicle. Another mode of administering the agents of theinvention may utilize a patch formulation to affect transdermaldelivery.

Agents may alternatively be administered in methods of this invention byinhalation, via the nasal or oral routes, e.g., in a spray formulationalso containing a suitable carrier.

Examples of agents useful in methods of the invention will now bedescribed by reference to illustrative synthetic schemes for theirgeneral preparation below and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Unless otherwise specified, the variables are asdefined above in reference to Formula (I).

In the Schemes depicted below, one skilled in the art will recognizethat R¹¹ may be replaced with a suitable nitrogen protecting group, suchas a tert-butoxycarbonyl group (Boc), and that protecting group replacedat a later stage in the synthesis.

Referring to Scheme A, amines A2 are commercially available or areprepared from acids A1 or alcohols A3. Coupling of acids A1 with aminesR⁶NH₂, in the presence of activating agents such asdicyclohexyl-carbodiimide, EDC/HOBt, or carbonyl diimidazole, in asolvent such as DMF or THF, provides the corresponding amides (notshown). Alternatively, acids A1 are activated to their correspondingacid chlorides and reacted with amines R⁶NH₂ in the presence of asuitable base such as triethylamine or diisopropylethylamine, in asolvent such as DCM or THF. The resulting amides are reduced to aminesA2 by a suitable reducing agent such as LiAlH₄, in a solvent such asTHF. Alcohols A3 are activated using general methods to form, forexample, alkyl halides or alkyl tosylates. Displacement with R⁶NH₂ inthe presence of a suitable base such as NaH, NaOH, triethylamine, ordiisopropylethylamine, in a solvent such as DCM or THF, provides aminesA2. Alternatively, amines A2 are prepared from alcohols A3 by reactionwith phthalimide or a suitable amino surrogate under Mitsunobuconditions. Where phthalimide is used, the free amine is revealedthrough treatment with hydrazine.

Referring to Scheme B, amines A2 are reacted with pyrimidines B1, whichare commercially available or are prepared by oxidation of commerciallyavailable alkylsulfanyl pyrimidines, or by other general methods, in asolvent such as pyridine, DMF, MeOH, or EtOH, or a mixture thereof, attemperatures between about room temperature and the reflux temperatureof the solvent, or in a sealed tube at temperatures up to about 120° C.2-Aminopyrimidines B2 are converted to aldehydes B3 by reduction of theY substituent with a suitable reducing agent such as diisobutylaluminumhydride. Where Y is an ester group, reduction produces aldehydes B3 orthe corresponding alcohols (not shown). Where an alcohol is produced,oxidation using a suitable oxidizing agent such as MnO₂, Dess-Martinperiodinane, or Swern conditions, provides aldehydes B3. Condensation ofaldehydes B3 with suitably substituted diamines B4, in the presence of adehydrating agent such as NaH₂S₂O₅, in a solvent such as DMF, MeOH, orEtOH, or a mixture thereof, at temperatures between about roomtemperature and the reflux temperature of the solvent, producescompounds of Formula (I).

Referring to Scheme C, acids A1 or alcohols A3 may be coupled with2-aminopyrimidines C1 using the methods described in Scheme A to formamides and amines C2. Compounds C2 are processed as described in SchemeB to provide compounds of Formula (I).

Referring to Scheme D, amines A2 are reacted with pyrazines D1, whichare commercially available or are prepared by general methods, in asolvent such as pyridine, MeOH, or EtOH, or a mixture thereof, attemperatures between about room temperature and the reflux temperatureof the solvent, or in a sealed tube at temperatures up to about 120° C.2-Aminopyrazines D2 are processed into compounds of Formula (I) as shownin Scheme D using methods analogous to those described in Scheme B.

Additional synthetic methods are described in U.S. Pat. Appl. Publ.200510070550A1, which is hereby incorporated by reference.

Compounds prepared according to the schemes described above may beobtained as single enantiomers, diastereomers, or regioisomers, or asracemic mixtures or mixtures of enantiomers, diastereomers, orregioisomers. Where regioisomeric or diastereomeric mixtures areobtained, isomers may be separated using conventional methods such aschromatography or crystallization. Where racemic (1:1) and non-racemic(not 1:1) mixtures of enantiomers are obtained, single enantiomers maybe isolated using conventional separation methods known to one skilledin the art. Particularly useful separation methods may include chiralchromatography, recrystallization, diastereomeric salt formation, orderivatization into diastereomeric adducts followed by separation.

The following examples are provided to further illustrate aspects of theinvention and various preferred embodiments.

EXAMPLES Chemistry:

In obtaining the compounds described in the examples below and thecorresponding analytical data, the following experimental and analyticalprotocols were followed unless otherwise indicated.

Unless otherwise stated, reaction mixtures were magnetically stirred atroom temperature (rt). Where solutions are “dried,” they are generallydried over a drying agent such as Na₂SO₄ or MgSO₄. Where mixtures,solutions, and extracts were “concentrated”, they were typicallyconcentrated on a rotary evaporator under reduced pressure.

Thin-layer chromatography was performed using Merck silica gel 60 F₂₅₄2.5 cm×7.5 cm 250 μm or 5.0 cm×10.0 cm 250 μm pre-coated silica gelplates. Preparative thin-layer chromatography was performed using EMScience silica gel 60 F₂₅₄ 20 cm×20 cm 0.5 mm pre-coated plates with a20 cm×4 cm concentrating zone.

Normal-phase flash column chromatography (FCC) was performed on silicagel (SiO₂) eluting with 2 M NH₃ in MeOH/DCM, unless otherwise noted.Reaction mixtures were loaded onto the SiO2 column without workup.

Reversed-phase HPLC was performed on a Hewlett Packard HPLC Series 1100,with a Phenomenex Luna C18 (5 μm, 4.6×150 mm) column. Detection was doneat λ=230, 254 and 280 nm. The gradient was 10 to 99% acetonitrile/water(0.05% trifluoroacetic acid) over 5.0 min with a flow rate of 1 mL/min.Alternatively, HPLC was performed on a Dionex APS2000 LC/MS with aPhenomenex Gemini C18 (5 μm, 30×100 mm) column, and a gradient of 5 to100% acetonitrile/water (20 mM NH₄OH) over 16.3 min, and a flow rate of30 mL/min.

Mass spectra (MS) were obtained on an Agilent series 1100 MSD usingelectrospray ionization (ESI) in positive mode unless otherwiseindicated. Calculated (calcd.) mass corresponds to the exact mass.

Nuclear magnetic resonance (NMR) spectra were obtained on Bruker modelDRX spectrometers. The format of the ¹H NMR data below is: chemicalshift in ppm downfield of the tetramethylsilane reference (multiplicity,coupling constant J in Hz, integration).

Chemical names were generated using ChemDraw Version 6.0.2(CambridgeSoft, Cambridge, Mass.).

Example 1[5-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

Step A; 4-Methyl-2-ethylsulfanyl-pyrimidine-5-carboxylic acid ethylester

A mixture of ethyl acetoacetate (6.37 mL, 50.0 mol), dimethylformamidedimethylacetal (8.94 g, 75.0 mmol), and catalytic p-toluenesulfonic acidwas heated at 100° C. for 2 h. After cooling to rt, the mixture wasdiluted with N,N-dimethylformamide (DMF; 50 mL) and 2-ethylisothioureahydrobromide (9.10 g, 50.0 mmol) was added. After heating the at 100° C.for 18 h, the mixture was cooled to rt and concentrated to give a cruderesidue, which was purified by FCC (EtOAc/hexanes) to give 7.1 g (61%)of a solid. ¹H NMR (CDCl₃): 8.97-8.91 (m, 1H), 4.43-4.35 (m, 2H),3.24-3.15 (m, 2H), 2.81-2.72 (m, 3H), 1.47-1.35 (m, 6H).

Step B; 2-Ethanesulfonyl-4-methyl-pyrimidine-5-carboxylic acid ethylester

To a 0° C. solution of 4-methyl-2-ethylsulfanyl-pyrimidine-5-carboxylicacid ethyl ester (3 g, 13.3 mmol) in dichloromethane (DCM; 50 mL) wasadded urea hydrogen peroxide (5.20 g, 55.7 mmol) followed bytrifluoroacetic anhydride (7.39 mL, 53.1 mmol) dropwise. The solutionwas warmed to rt for 2 h before quenching with satd. aq. Na₂S₂O₃ (20 mL)and extracting with DCM (100 mL). The organic layer was dried (Na₂SO₄)and concentrated to give 1.50 g of an orange solid which was usedimmediately in the next step without purification. ¹H NMR (CDCl₃): 9.28(s, 1H), 4.47 (q, J=7.2 Hz, 2H), 3.60 (q, J=7.5 Hz, 2H), 2.96 (s, 3H),1.47-1.42 (m, 6H).

Step C;4-Methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carboxylicacid ethyl ester

A mixture of 2-ethanesulfonyl-4-methyl-pyrimidine-5-carboxylic acidethyl ester (0.30 g, 1.18 mmol) and3-(1-methyl-piperidin-4-yl)-propylamine (0.18 mg, 1.10 mmol) in EtOH (3mL) was heated in a sealed tube at 100° C. for 6 h. The mixture wasconcentrated and purified by FCC to give 200 mg (53%). ¹H NMR (CDCl₃):8.88-8.72 (m, 1H), 5.60-5.44 (m, 1H), 4.31 (q, J=7.2 Hz, 2H), 3.52-3.39(m, 2H), 2.91-2.77 (m, 2H), 2.64 (s, 3H), 2.26 (s, 3H), 1.94-1.85 (m,2H), 1.72-1.57 (m, 4H), 1.41-1.20 (m, 8H).

Step D;{4-Methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidin-5-yl}-methanol

To a 0° C. solution of4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carboxylicacid ethyl ester (0.20 g, 0.63 mmol) in THF (6 mL) was addeddiisobutylaluminum hydride (1 M in hexanes; 1.25 mL, 1.25 mmol)dropwise. The mixture was warmed to rt over 1 h. The reaction wasquenched with 1 M H₂SO₄ (2 mL). The mixture was neutralized with satd.aq. NaHCO₃, and diluted with MeOH (2 mL), CHCl₃ (10 mL), and satd. aq.sodium potassium tartrate (10 mL). The mixture was stirred vigourouslyuntil the layers separated. The organic layer was dried (Na₂SO₄) andconcentrated to give the crude product (138 mg), which was used in thenext step without further purification. ¹H NMR (CDCl₃): 8.07 (s, 1H),4.52 (s, 2H), 3.42-3.33 (m, 2H), 2.88-2.74 (m, 2H), 2.41 (s, 3H), 2.23(s, 3H), 1.93-1.83 (m, 2H), 1.72-1.53 (m, 4H), 1.35-1.16 (m, 5H).

Step E;[5-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

A mixture of4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidin-5-yl}-methanol(0.14 g, 0.49 mmol) in toluene (3 mL) was added MnO₂ (0.22 g, 2.48mmol). After 30 min at 70° C., the mixture was filtered throughdiatomaceous earth. The filtrate was concentrated and immediatelydissolved in DMF. A portion of this solution (corresponding to 0.05 mg,0.17 mmol of4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carbaldehyde)was then treated with 4-fluoro-3-methyl-benzene-1,2-diamine (1.1 equiv.)and Na₂H₂S₂O₅ (1.25 equiv.) at 90° C. for 12 h. The reaction mixture waspurified by FCC to afford the title compound. MS: mass calcd. forC₂₂H₂₉FN₆, 396.24; m/z found, 397.2 [M+H]⁺. ¹H NMR (CD₃OD): 8.62 (s,1H), 7.55 (dd, J=8.0, 3.9 Hz, 1H), 7.17 (dd, J=10.3, 8.8 Hz, 1H), 3.60(t, J=6.9 Hz, 2H), 3.10-2.99 (m, 2H), 2.71 (s, 3H), 2.66 (d, J=1.4 Hz,3H), 2.44 (s, 3H), 2.26-2.17 (m, 2H), 1.98-1.88 (m, 2H), 1.87-1.77 (m,2H), 1.55-1.36 (m, 5H).

The following compounds in Examples 2-14 were synthesized analogously tothe procedures described in Example 1.

Example 2[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS: mass calcd. for C₂₃H₃₂N₆, 392.27; m/z found, 393.3 [M+H]⁺. ¹H NMR(CD₃OD): 8.43 (s, 1H), 7.20 (s, 1H), 6.89 (s, 1H), 3.41 (t, J=7.0 Hz,2H), 2.89-2.82 (m, 2H), 2.54 (s, 3H), 2.53 (s, 3H), 2.42 (s, 3H), 2.25(s, 3H), 2.05-1.96 (m, 2H), 1.78-1.70 (m, 2H), 1.69-1.59 (m, 2H),1.34-1.21 (m, 5H).

Example 3[5-(6-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS: mass calcd. for C₂₂H₂₉FN₆, 396.24; m/z found, 397.3 [M+H]⁺. ¹H NMR(CD₃OD): 8.45 (s, 1H), 7.10 (dd, J=8.9, 2.1 Hz, 1H), 6.85 (dd, J=10.5,1.5 Hz, 1H), 3.42 (t, J=7.0 Hz, 2H), 2.90-2.82 (m, 2H), 2.58 (s, 3H),2.54 (s, 3H), 2.25 (s, 3H), 2.05-1.93 (m, 2H), 1.78-1.71 (m, 2H),1.69-1.60 (m, 2H), 1.39-1.18 (m, 5H).

Example 4[5-(4,5-Difluoro-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS: mass calcd. for C₂₁H₂₆F₂N₆, 400.22; m/z found, 401.2 [M+H]⁺. ¹H NMR(CD₃OD): 8.49 (s, 1H), 7.32 (ddd, J=8.8, 3.7, 1.1 Hz, 1H), 7.17 (ddd,J=11.4, 8.8, 7.2 Hz, 1H), 3.43 (t, J=7.0 Hz, 2H), 2.93-2.82 (m, 2H),2.58 (s, 3H), 2.27 (s, 3H), 2.08-1.97 (m, 2H), 1.79-1.71 (m, 2H),1.70-1.60 (m, 2H), 1.40-1.16 (m, 5H).

Example 5[5-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS: mass calcd. for C₂₃H₃₂N₆, 392.27; m/z found, 393.3 [M+H]⁺. ¹H NMR(CD₃OD): 8.44 (s, 1H), 7.31 (d, J=7.7 Hz, 1H), 7.07 (d, J=8.2 Hz, 1H),3.43 (t, J=7.3 Hz, 1H), 2.92-2.82 (m, 2H), 2.53 (s, 3H), 2.51 (s, 3H),2.39 (s, 3H), 2.26 (s, 3H), 2.07-1.96 (m, 2H), 1.79-1.71 (m, 2H),1.71-1.61 (m, 2H), 1.41-1.16 (m, 5H).

Example 6[5-(4,6-Difluoro-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS: mass calcd. for C₂₁H₂₆F₂N₆, 400.22; m/z found, 401.2 [M+H]⁺. ¹H NMR(CD₃OD): 8.48 (s, 1H), 7.13 (dd, J=8.5, 2.1 Hz, 1H), 6.88 (dt, J=10.4,10.4, 2.2 Hz, 1H), 3.42 (t, J=6.9 Hz, 2H), 2.91-2.82 (m, 2H), 2.57 (s,3H), 2.26 (s, 3H), 2.07-1.97 (m, 2H), 1.80-1.71 (m, 2H), 1.70-1.59 (m,2H), 1.40-1.17 (m, 5H).

Example 7[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-methyl-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS: mass calcd. for C₂₄H₃₄N₆, 406.28; m/z found, 407.3 [M+H]⁺. ¹H NMR(CD₃OD): 8.31 (s, 1H), 7.04 (s, 1H), 6.73 (s, 1H), 3.55 (t, J=7.3 Hz,2H), 3.04 (s, 3H), 2.75-2.67 (m, 2H), 2.39 (s, 6H), 2.26 (s, 3H), 2.10(s, 3H), 1.90-1.82 (m, 2H), 1.63-1.47 (m, 4H), 1.17-1.01 (m, 5H).

Example 8[5-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-4-ethyl-pyrimidin-2-yl]-methyl-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS: mass calcd. for C₂₄H₃₄N₆, 406.28; m/z found, 407.3 [M+H]⁺. ¹H NMR(CD₃OD): 8.37 (s, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.06 (d, J=8.2 Hz, 1H),3.43 (t, J=6.2 Hz, 2H), 2.94-2.81 (m, 4H), 2.50 (s, 3H), 2.39 (s, 3H),2.25 (s, 3H), 2.05-1.95 (m, 2H), 1.79-1.70 (m, 2H), 1.71-1.61 (m, 2H),1.40-1.10 (m, 8H).

Example 9[5-(4,5-Difluoro-1H-benzoimidazol-2-yl)-4-ethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS: mass calcd. for C₂₂H₂₈F₂N₆, 414.23; m/z found, 415.3 [M+H]⁺. ¹H NMR(CD₃OD): 8.42 (s, 1H), 7.32 (ddd, J=8.8, 3.6, 1.2 Hz, 1H), 7.17 (ddd,J=11.4, 8.8, 7.2 Hz, 1H), 3.48-3.39 (m, 2H), 3.01-2.91 (m, 2H),2.90-2.83 (m, 2H), 2.26 (s, 3H), 2.07-1.96 (m, 2H), 1.79-1.60 (m, 4H),1.38-1.11 (m, 8H).

Example 10[5-(4-Fluoro-5-methyl-1H-benzoimidazol-2-yl)-4-propyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS: mass calcd. for C₂₄H₃₃FN₆, 424.28; m/z found, 425.3 [M+H]⁺. ¹H NMR(CD₃OD): 8.39 (s, 1H), 7.37 (dd, J=8.5, 4.2 Hz, 1H), 7.00 (dd, J=10.3,8.9 Hz, 1H), 3.43 (t, J=6.4 Hz, 2H), 2.91-2.82 (m, 4H), 2.49 (d, J=1.4Hz, 3H), 2.25 (s, 3H), 2.05-1.96 (m, 2H), 1.81-1.57 (m, 6H), 1.40-1.16(m, 5H), 0.90-0.83 (m, 3H).

Example 11[5-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-4-isopropyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS: mass calcd. for C₂₅H₃₆N₆, 420.30; m/z found, 421.3 [M+H]⁺. ¹H NMR(CD₃OD): 8.30 (s, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.07 (d, J=8.2 Hz, 1H),3.47-3.38 (m, 3H), 2.94-2.73 (m, 2H), 2.50 (s, 3H), 2.39 (s, 3H), 2.25(s, 3H), 2.05-1.91 (m, 2H), 1.80-1.60 (m, 4H), 1.40-1.21 (m, 5H), 1.19(d, J=6.7 Hz, 6H).

Example 12[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-isopropyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS: mass calcd. for C₂₅H₃₆N₆, 420.30; m/z found, 421.3 [M+H]⁺. ¹H NMR(CD₃OD): 8.29 (s, 1H), 7.19 (s, 1H), 6.90 (s, 1H), 3.50-3.37 (m, 3H),3.07-2.97 (m, 2H), 2.54 (s, 3H), 2.43 (s, 3H), 2.40 (s, 3H), 2.30-2.20(m, 2H), 1.85-1.78 (m, 2H), 1.73-1.64 (m, 2H), 1.42-1.26 (m, 5H), 1.19(d, J=6.7 Hz, 6H).

Example 13[4-Cyclobutyl-5-(4,5-dimethyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS: mass calcd. for C₂₆H₃₆N₆, 432.30; m/z found, 433.3 [M+H]⁺. ¹H NMR(CD₃OD): 8.31 (s, 1H), 7.31 (d, J=7.7 Hz, 1H), 7.06 (d, J=8.2 Hz, 1H),4.02 (p, J=8.4 Hz, 1H), 3.57-3.38 (m, 2H), 2.93-2.81 (m, 2H), 2.50 (s,3H), 2.39 (s, 3H), 2.38-2.32 (m, 2H), 2.26 (s, 3H), 2.14-1.86 (m, 5H),1.87-1.61 (m, 5H), 1.43-1.18 (m, 5H).

Example 14[4-Cyclobutyl-5-(4,5-difluoro-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS: mass calcd. for C₂₄H₃₀F₂N₆, 440.25; m/z found, 441.3 [M+H]⁺. ¹H NMR(CD₃OD): 8.36 (s, 1H), 7.32 (ddd, J=8.8, 3.6, 1.1 Hz, 1H), 7.17 (ddd,J=11.4, 8.8, 7.2 Hz, 1H), 4.10 (p, J=8.4 Hz, 1H), 3.57-3.39 (m, 2H),2.92-2.81 (m, 2H), 2.42-2.29 (m, 2H), 2.27-2.24 (m, 3H), 2.19-2.06 (m,2H), 2.06-1.94 (m, 2H), 1.90-1.60 (m, 6H), 1.40-1.14 (m, 5H).

Example 15[5-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

The title compound was prepared from2-methylsulfanyl-pyrimidine-5-carboxylic acid methyl ester (Zhichkin, P.et al., Synthesis 2002, 6, 720-722) using methods analogous to thosedescribed in Example 1. MS: mass calcd. for C₂₁H₂₇FN₆, 382.23; m/zfound, 383.4 [M+H]⁺. ¹H NMR (CD₃OD): 9.02-8.85 (m, 2H), 7.45-7.27 (m,1H), 6.98 (dd, J=10.1, 8.9 Hz, 1H), 3.43 (t, J=7.1 Hz, 2H), 2.96-2.88(m, 2H), 2.51 (s, 3H), 2.30 (s, 3H), 2.14-2.03 (m, 2H), 1.83-1.72 (m,2H), 1.72-1.61 (m, 2H), 1.41-1.18 (m, 5H).

The compounds in Examples 16-32 were prepared using methods analogous tothose described in Example 1.

Example 16[4-Cyclobutyl-5-(5-fluoro-4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS: mass calcd. for C₂₅H₃₃FN₆, 436.28; m/z found, 437.3 [M+H]⁺.

Example 17[4-Cyclobutyl-5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS: mass calcd. for C₂₆H₃₆N₆, 432.30; m/z found, 433.3 [M+H]⁺.

Example 18[5-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-4-propyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS: mass calcd. for C₂₅H₃₆N₆, 420.30; m/z found, 421.3 [M+H]⁺.

Example 19[4-Ethyl-5-(5-fluoro-4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS: mass calcd. for C₂₃H₃₁FN₆, 410.26; m/z found, 411.3 [M+H]⁺.

Example 20[5-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-isopropyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS: mass calcd. for C₂₄H₃₃FN₆, 424.28; m/z found, 425.3 [M+H]⁺.

Example 21[4-Methyl-5-(4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS: mass calcd. for C₂₂H₃₀N₆, 378.25; m/z found, 379.3 [M+H]⁺.

Example 22[5-(1H-Benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS: mass calcd. for C₂₁H₂₈N₆, 364.24; m/z found, 365.2 [M+H]⁺.

Example 23[5-(5-Fluoro-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS: mass calcd. for C₂₁H₂₇FN₆, 382.23; m/z found, 383.2 [M+H]⁺.

Example 24[3-(1-Methyl-piperidin-4-yl)-propyl]-[4-methyl-5-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-amine

MS: mass calcd. for C₂₂H₂₇F₃N₆, 432.22; m/z found, 433.2 [M+H]⁺.

Example 25[5-(5-tert-Butyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS: mass calcd. for C₂₅H₃₆N₆, 420.30; m/z found, 421.3 [M+H]⁺.

Example 26[5-(5-Chloro-4-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS: mass calcd. for C₂₂H₂₉ClN₆, 412.21; m/z found, 413.2 [M+H]⁺.

Example 27[5-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-trifluoromethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS: mass calcd. for C₂₂H₂₆F₄N₆, 450.22; m/z found, 451.2 [M+H]⁺.

Example 28[5-(6-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-trifluoromethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS: mass calcd. for C₂₂H₂₆F₄N₆, 450.22; m/z found, 451.2 [M+H]⁺.

Example 29[5-(4,6-Dichloro-1H-benzoimidazol-2-yl)-4-trifluoromethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS: mass calcd. for C₂₁H₂₃Cl₂F₃N₆, 486.13; m/z found, 487.1 [M+H]⁺.

Example 30[5-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-4-trifluoromethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS: mass calcd. for C₂₃H₂₉F₃N₆, 446.24; m/z found, 447.3 [M+H]⁺.

Example 31[5-(5,6-Difluoro-1H-benzoimidazol-2-yl)-4-trifluoromethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS: mass calcd. for C₂₁H₂₃F₅N₆, 454.19; m/z found, 455.2 [M+H]⁺.

Example 32[5-(4,5-Difluoro-1H-benzoimidazol-2-yl)-4-isopropyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS: mass calcd. for C₂₃H₃₀F₂N₆, 428.25; m/z found, 429.3 [M+H]⁺.

Example 33[5-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-pyrazin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

Step A;5-[3-(1-Methyl-piperidin-4-yl)-propylamino]-pyrazine-2-carboxylic acidmethyl ester

A solution of 5-chloro-pyrazine-2-carboxylic acid methyl ester (1equiv.) and 3-(1-methyl-piperidin-4-yl)-propylamine (1.1 equiv.) in MeOH(0.25 M) heated at 100° C. in a sealed tube for 4 h. The mixture wascooled to rt and concentrated to give a crude product which was purifiedby FCC.

Step B;5-[3-(1-Methyl-piperidin-4-yl)-propylamino]-pyrazine-2-carbaldehyde

A −78° C. solution of5-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrazine-2-carboxylic acidmethyl ester in DCM (0.1 M) was treated with diisobutylaluminum hydride(1 M in hexanes; 1 equiv.) dropwise. The reaction was quenched with 1 MH₂SO₄, neutralized with satd. aq. NaHCO₃, and diluted with MeOH, CHCl₃,and satd. aq. sodium potassium tartrate. The mixture was stirredvigourously until the layers separated. The organic layer was dried(Na₂SO₄) and concentrated to give the crude product, which was used inthe next step without further purification.

Step C.

The title compound was prepared using methods analogous to thosedescribed in Example 1, Step E, Part 2, to provide the title compound.MS: mass calcd. for C₂₁H₂₇FN₆, 382.23; m/z found, 383.2 [M+H]⁺.

Example 34[5-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-pyrazin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

The title compound was prepared using methods analogous to thosedescribed in Example 33. MS: mass calcd. for C₂₂H₃₀N₆, 378.25; m/zfound, 379.3 [M+H]⁺.

The compounds in Examples 35-50 were prepared using methods analogous tothose described in the preceding examples.

Example 35[5-(4,6-Bis-trifluoromethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS (ESI): mass calcd. for C₂₃H₂₆F₆N₆, 500.49; m/z found, 501.2 [M+H]⁺.

Example 362-{4-Methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidin-5-yl}-1H-benzoimidazole-5-carbonitrile

MS (ESI): mass calcd. for C₂₂H₂₇N₇, 389.51; m/z found, 390.3 [M+H]⁺. ¹HNMR (MeOD): 8.55 (s, 1H), 7.99 (dd, J=1.3, 0.5 Hz, 1H), 7.72 (dd, J=8.3,0.5 Hz, 1H), 7.57 (dd, J=8.4, 1.5 Hz, 1H), 3.43 (t, J=6.8 Hz, 2H), 2.89(d, J=12.1 Hz, 2H), 2.62 (s, 3H), 2.28 (s, 3H), 2.05 (t, J=11.8 Hz, 2H),1.76 (d, J=11.3 Hz, 2H), 1.66 (td, J=14.7, 7.5 Hz, 2H), 1.30 (m, 5H).

Example 37[5-(5-Methoxy-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS (ESI): mass calcd. for C₂₂H₃₀N₆O, 394.52; m/z found, 395.3 [M+H]⁺. ¹HNMR (MeOD): 8.45 (s, 1H), 7.46 (s, J=8.8 Hz, 1H), 6.90 (dd, J=8.8, 2.4Hz, 1H), 7.09 (s, 1H), 3.85 (s, 3H), 3.42 (t, J=7.1 Hz, 2H), 2.88 (d,J=11.9 Hz, 2H), 2.56 (s, 3H), 2.27 (s, 3H), 2.03 (t, J=11.7 Hz, 2H),1.75 (d, J=12.7 Hz, 2H), 1.66 (td, J=15.0, 7.6 Hz, 2H), 1.38-1.20 (m,5H).

Example 38[5-(4-Chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS (ESI): mass calcd. for C₂₂H₂₆ClF₃N₆, 466.94; m/z found, 467.2 [M+H]⁺.¹H NMR (MeOD): 8.55 (s, 1H), 7.83 (s, 1H), 7.55-7.53 (m, 1H), 3.43 (t,J=6.9 Hz, 2H), 2.88 (d, J=11.9 Hz, 2H), 2.61 (s, 3H), 2.27 (s, 3H), 2.04(t, J=11.8 Hz, 2H), 1.75 (d, J=12.0 Hz, 2H), 1.66 (m, 2H), 1.38-1.18 (m,5H).

Example 39[5-(5-Chloro-6-fluoro-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS (ESI): mass calcd. for C₂₁H₂₆ClFN₆, 416.93; m/z found, 417.2 [M+H]⁺.¹H NMR (MeOD): 8.49 (s, 1H), 7.67 (d, J=6.6 Hz, 1H), 7.44 (d, J=9.3 Hz,1H), 3.42 (t, J=7.0 Hz, 2H), 2.87 (d, J=11.9 Hz, 2H), 2.58 (s, 3H), 2.25(s, 3H), 2.01 (t, J=12.7 Hz, 2H), 1.74 (d, J=12.1 Hz, 2H), 1.65 (dd,J=14.8, 7.2 Hz, 2H), 1.41-1.16 (m, 5H).

Example 40[5-(5-Chloro-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS (ESI): mass calcd. for C₂₁H₂₇ClN₆, 398.94; m/z found, 399.2 [M+H]⁺.¹H NMR (MeOD): 8.49 (s, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.55 (d, J=8.6 Hz,1H), 7.25 (dd, J=8.6, 2.0 Hz, 1H), 3.42 (t, J=6.9 Hz, 2H), 2.87 (d,J=12.0 Hz, 2H), 2.58 (s, 3H), 2.26 (s, 3H), 2.02 (t, J=11.7 Hz, 2H),1.75 (d, J=12.1 Hz, 2H), 1.65 (td, J=14.8, 7.4 Hz, 2H), 1.38-1.19 (m,5H).

Example 41[5-(5,6-Dichloro-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS (ESI): mass calcd. for C₂₁H₂₆Cl₂N₆, 433.39; m/z found, 433.2 [M+H]⁺.¹H NMR (MeOD): 8.50 (s, 1H), 7.74 (s, 2H), 3.43 (t, J=7.1 Hz, 2H), 2.93(d, J=11.6 Hz, 2H), 2.59 (s, 3H), 2.31 (s, 3H), 2.11 (t, J=11.3 Hz, 2H),1.78 (d, J=12.4 Hz, 2H), 1.66 (m, 2H), 1.33 (m, 6H).

Example 42[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-ethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS (ESI): mass calcd. for C₂₄H₃₄N₆, 406.58; m/z found, 407.3 [M+H]⁺. ¹HNMR (MeOD): 8.36 (s, 1H), 7.19 (s, 1H), 6.89 (s, 1H), 3.46-3.39 (m, 2H),2.88 (dd, J=15.1, 7.8 Hz, 4H), 2.54 (s, 3H), 2.42 (s, 3H), 2.26 (s, 3H),2.01 (t, J=10.9 Hz, 2H), 1.74 (d, J=11.9 Hz, 2H), 1.66 (dd, J=14.4, 7.2Hz, 2H), 1.26 (m, 8H).

Example 43[4-Ethyl-5-(4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS (ESI): mass calcd. for C₂₃H₃₂N₆, 392.55; m/z found, 393.3 [M+H]⁺. ¹HNMR (MeOD): 8.39 (s, 1H), 7.41 (d, J=7.7 Hz, 1H), 7.15 (t, J=7.7 Hz,1H), 7.05 (d, J=7.3 Hz, 1H), 3.44 (t, J=5.2 Hz, 2H), 2.89 (s, 4H), 2.58(s, 3H), 2.27 (s, 3H), 2.03 (t, J=11.7 Hz, 2H), 1.75 (d, J=12.4 Hz, 2H),1.67 (td, J=14.9, 7.3 Hz, 2H), 1.41-1.12 (m, 8H).

Example 44[4-Cyclopropyl-5-(4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS (ESI): mass calcd. for C₂₄H₃₂N₆, 404.56; m/z found, 405.3 [M+H]⁺. ¹HNMR (MeOD): 8.32 (s, 1H), 7.41 (d, J=6.5 Hz, 1H), 7.17-7.12 (m, 1H),7.05 (d, J=7.3 Hz, 1H), 3.39-3.34 (m, 2H), 2.89 (d, J=12.0 Hz, 2H), 2.59(s, 3H), 2.47 (s, 1H), 2.28 (s, 3H), 2.05 (t, J=11.6 Hz, 2H), 1.75 (d,J=12.0 Hz, 2H), 1.67-1.58 (m, 2H), 1.38-1.17 (m, 7H), 1.02 (dd, J=7.3,3.0 Hz, 2H).

Example 45[4-Cyclopropyl-5-(4,5-dimethyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS (ESI): mass calcd. for C₂₅H₃₄N₆, 418.59; m/z found, 419.3 [M+H]⁺. ¹HNMR (MeOD): 8.31 (s, 1H), 7.31 (d, J=7.2 Hz, 1H), 7.06 (d, J=8.2 Hz,1H), 3.36 (t, J=7.1 Hz, 2H), 2.88 (d, J=12.0 Hz, 2H), 2.56-2.42 (m, 4H),2.39 (s, 3H), 2.27 (s, 3H), 2.03 (t, J=11.6 Hz, 2H), 1.74 (d, J=11.7 Hz,2H), 1.62 (td, J=14.7, 7.5 Hz, 2H), 1.38-1.16 (m, 7H), 1.01 (dd, J=7.5,3.1 Hz, 2H).

Example 46[4-Cyclopropyl-5-(6-fluoro-4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS (ESI): mass calcd. for C₂₄H₃₁FN₆, 422.55; m/z found, 423.3 [M-FH]⁺.¹H NMR (MeOD): 8.32 (s, 1H), 7.10 (d, J=8.0 Hz, 1H), 6.86 (dd, J=10.5,1.5 Hz, 1H), 3.36 (t, J=7.3 Hz, 2H), 2.91 (d, J=12.1 Hz, 2H), 2.59 (s,3H), 2.48 (s, 1H), 2.29 (s, 3H), 2.07 (t, J=10.8 Hz, 2H), 1.76 (d,J=12.3 Hz, 2H), 1.62 (dd, J=14.3, 7.4 Hz, 2H), 1.40-1.17 (m, 7H),1.05-0.98 (m, 2H).

Example 47[4-Cyclopropyl-5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS (ESI): mass calcd. for C₂₅H₃₄N₆, 418.59; m/z found, 419.3 [M+H]⁺. ¹HNMR (MeOD): 8.30 (s, 1H), 7.20 (s, 1H), 6.89 (s, 1H), 3.36 (t, J=7.0 Hz,2H), 2.88 (d, J=11.5 Hz, 2H), 2.54 (s, 3H), 2.46 (s, 1H), 2.42 (s, 3H),2.27 (s, 3H), 2.03 (t, J=11.0 Hz, 2H), 1.74 (d, J=11.4 Hz, 2H),1.66-1.57 (m, 2H), 1.38-1.16 (m, 7H), 1.04-0.98 (m, 2H).

Example 48[4-Cyclopropyl-5-(5-fluoro-4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

MS (ESI): mass calcd. for C₂₄H₃₁FN₆, 422.55; m/z found, 423.3 [M-FH]⁺.¹H NMR (MeOD): 8.33 (s, 1H), 7.38 (s, 1H), 7.01 (dd, J=10.3, 8.8 Hz,1H), 3.37 (t, J=7.0 Hz, 1H), 2.91 (d, J=11.9 Hz, 2H), 2.54-2.43 (m, 4H),2.30 (s, 3H), 2.08 (t, J=10.9 Hz, 2H), 1.94 (s, 1H), 1.76 (d, J=12.4 Hz,2H), 1.68-1.59 (m, 2H), 1.42-1.17 (m, 7H), 1.06-1.00 (m, 2H).

The compounds in Examples 49-50 are prepared using methods analogous tothose described in the preceding examples.

Example 49[5-(6-Chloro-5-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

Example 50[5-(4-Chloro-6-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

Additional examples of embodiments of this invention are provided byhemitartrate salts of compounds of Formula (I) and by hydrates, such asmonohydrates and dihydrates, of compounds of Formula (I). For example,embodiments of this invention include hydrates, such as monohydrates anddihydrates of, and/or hemitartrate salts of compounds selected from thegroup consisting of:

-   [5-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [5-(6-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [5-(4,5-Difluoro-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [5-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [5-(4,6-Difluoro-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-methyl-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [5-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-4-ethyl-pyrimidin-2-yl]-methyl-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [5-(4,5-Difluoro-1H-benzoimidazol-2-yl)-4-ethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [5-(4-Fluoro-5-methyl-1H-benzoimidazol-2-yl)-4-propyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [5-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-4-isopropyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-isopropyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [4-Cyclobutyl-5-(4,5-dimethyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [4-Cyclobutyl-5-(4,5-difluoro-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [5-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [4-Cyclobutyl-5-(5-fluoro-4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [4-Cyclobutyl-5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [5-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-4-propyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [4-Ethyl-5-(5-fluoro-4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [5-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-isopropyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [4-Methyl-5-(4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [5-(1H-Benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [5-(5-Fluoro-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [3-(1-Methyl-piperidin-4-yl)-propyl]-[4-methyl-5-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-amine;-   [5-(5-tert-Butyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [5-(5-Chloro-4-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [5-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-trifluoromethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [5-(6-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-trifluoromethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [5-(4,6-Dichloro-1H-benzoimidazol-2-yl)-4-trifluoromethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [5-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-4-trifluoromethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [5-(5,6-Difluoro-1H-benzoimidazol-2-yl)-4-trifluoromethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [5-(4,5-Difluoro-1H-benzoimidazol-2-yl)-4-isopropyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [5-(1H-Benzoimidazol-2-yl)-pyrazin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [5-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-pyrazin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [5-(4,6-Bis-trifluoromethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   2-{4-Methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidin-5-yl}-1H-benzoimidazole-5-carbonitrile;-   [5-(5-Methoxy-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [5-(4-Chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [5-(5-Chloro-6-fluoro-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [5-(5-Chloro-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [5-(5,6-Dichloro-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-ethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [4-Ethyl-5-(4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [4-Cyclopropyl-5-(4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [4-Cyclopropyl-5-(4,5-dimethyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [4-Cyclopropyl-5-(6-fluoro-4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [4-Cyclopropyl-5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [4-Cyclopropyl-5-(5-fluoro-4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;-   [5-(6-Chloro-5-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;    and-   [5-(4-Chloro-6-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine.

Biological Testing: Binding Assay on Recombinant Human Histamine H₄Receptor

SK-N-MC cells or COS7 cells were transiently transfected with pH4R andgrown in 150 cm² tissue culture dishes. Cells were washed with salinesolution, scraped with a cell scraper and collected by centrifugation(1000 rpm, 5 min). Cell membranes were prepared by homogenization of thecell pellet in 20 mM Tris-HCl with a polytron tissue homogenizer for 10sec at high speed. Homogenate was centrifuged at 1000 rpm for 5 min at4° C. The supernatant was then collected and centrifuged at 20,000×g for25 min at 4° C. The final pellet was resuspended in 50 mM Tris-HCl. Cellmembranes were incubated with ³H-histamine (5-70 nM) in the presence orabsence of excess histamine (10,000 nM). Incubation occurred at roomtemperature for 45 min. Membranes were harvested by rapid filtrationover Whatman GF/C filters and washed 4 times with ice-cold 50 mM TrisHCl. Filters were then dried, mixed with scintillant and counted forradioactivity. SK-N-MC or COS7 cells expressing human histamine H₄receptor were used to measure the affinity of binding of other compoundsand their ability to displace ³H-ligand binding by incubating theabove-described reaction in the presence of various concentrations ofinhibitor or compound to be tested. For competition binding studiesusing ³H-histamine, K, values were calculated, based on anexperimentally determined K_(D) value of 5 nM and a ligand concentrationof 5 nM, according to Y.-C. Cheng and W. H. Prusoff (Biochem. Pharmacol.1973, 22(23):3099-3108): K_(i)=(IC₅₀)/(1+([L]/(K_(D))). Results for thecompounds tested in this assay are presented in Table 1 as an average ofresults obtained, and rounded to the nearest 10 nM.

TABLE 1 EX K_(i) (nM) 1 21 2 11 3 4 4 11 5 4 6 17 7 83 8 29 9 210 10 47011 360 12 200 13 430 14 1010 15 290 16 1470 17 1320 18 2410 19 NT 20 23021 27 22 110 23 59 24 12 25 13 26 13 27 92 28 62 29 35 30 230 31 230 326110 33 250 34 680 35 11 36 170 37 81 38 2 39 15 40 7 41 6 42 22 43 11044 560 45 390 46 230 47 99 48 140

While the invention has been illustrated by reference to examples, it isunderstood that the invention is intended not to be limited to theforegoing detailed description.

What is claimed is:
 1. A hydrated hemitartrate salt of a compoundselected from:[5-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[5-(6-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-methyl-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[5-(4,6-Difluoro-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[4-Cyclobutyl-5-(4,5-dimethyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[4-Cyclobutyl-5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[4-Methyl-5-(4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-ethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[4-Cyclopropyl-5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[5-(4-Chloro-6-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[4-Ethyl-5-(5-fluoro-4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[5-(4-Chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[5-(1H-Benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;and[5-(4,5-dimethyl-1H-benzoimidazol-2-yl)-4-propyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine.2. A pharmaceutical composition comprising a pharmaceutically acceptableexcipient and an effective amount of at least one hydrated hemitartratesalt of a compound selected from:[5-(5-fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[5-(6-fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-methyl-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[5-(4,6-difluoro-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[4-cyclobutyl-5-(4,5-dimethyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[4-cyclobutyl-5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[4-methyl-5-(4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-ethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[4-cyclopropyl-5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[5-(4-chloro-6-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[4-ethyl-5-(5-fluoro-4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[5-(4-chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[5-(1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;and[5-(4,5-dimethyl-1H-benzoimidazol-2-yl)-4-propyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine.3. A compound selected from:[5-(5-fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[5-(6-fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-methyl-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[5-(4,6-difluoro-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[4-cyclobutyl-5-(4,5-dimethyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[4-cyclobutyl-5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[4-methyl-5-(4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-ethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[4-cyclopropyl-5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[5-(4-chloro-6-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[4-ethyl-5-(5-fluoro-4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[5-(4-chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[5-(1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;[5-(4,5-dimethyl-1H-benzoimidazol-2-yl)-4-propyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;and pharmaceutically acceptable salts thereof.
 4. A pharmaceuticalcomposition comprising a pharmaceutically acceptable excipient and atleast one compound as claimed in claim 3.